1. Field of the invention
The present invention relates to camptothecin-containing pharmaceutical compositions which, when stored for a long period of time or irradiated with light, undergo minimum degradation of camptothecin or a derivative thereof.
2. Background Art
Camptothecin (CPT) is an alkaloid contained in roots and fruit of Camptotheca acuminata, a deciduous tree native of China. Also, 7-ethyl-10-piperidinopiperidinocarbonyloxycamptothecin (CPT-11), which is a semi-synthetic derivative of CPT, is a particularly valuable substance for being a compound which exhibits high anti-tumor activity inherent to CPT and yet has a reduced toxicity (JP-B-1991-4077). The activity of CPT-11 is considered to be exhibited after CPT-11 is metabolized in the living body to be transformed to a semi-synthesized derivative, 7-ethyl-10-hydroxycamptothecin (SN-38) (JP-B-1987-47193).
CPT-11 is administered to a patient primarily via intravenous injection. Therefore, CPT-11 currently available on the market and distributed for use usually takes the form of an isotonic solution prepared in combination with sorbitol or physiological saline. A variety of attempts to prepare a drug product containing camptothecin have heretofore been carried out. For example, JP-A-1995-277981 discloses a sustained-release drug prepared by incorporating a camptothecin derivative into a copolymer of collagen and 2-hydroxyethylmethacrylate, and JP-A-1998-17472 discloses a sustained-release drug prepared by incorporating camptothecin or a derivative thereof into a carrier formed of a polylactic acid—glycolic acid copolymer.
Meanwhile, according to some knowledge which has heretofore been reported, a lactone-ring-open compound is formed in a CPT-11 drug, and this open-ring compound has no anti-tumor activity (Chem. Pharm. Bull. 42(10), 2135-2138 (1994)). Moreover, when irradiated with light, CPT-11 produces degradation products. Among the degradation products, D3, D2, and D3 have been reported to be three major structures (Drug Stability, Vol. 1 (2), 118 (1996)). Production of such impurities should be suppressed so as to prevent lowering of anti-tumor activity of the drug product and to avoid possible deviation from quality standards. Current camptothecin drug products are contained in light-shielding vials so as to prevent photodegradation of camptothecin. However, under typical light conditions inside a room, degradation is still observed if the drug products are stored for a long period of time. Also, in view that drug products may be placed under harsh conditions during distribution, further studies for preventing degradation are required.
Vials with light-shielding properties by nature have poor light permeability, which means that, during production steps or during storage-related quality tests, visual or mechanical inspection for any insoluble foreign matter is difficult to perform. Therefore, in the field of quality control or quality tests, use of transparent vials is keenly desired.